Sinusitis is a major health care problem for Americans of all ages. Despite the significant morbidity it causes and the enormous cost of managing this problem, little progress has been made at improving our basic understanding of its pathophysiology. The main constraints on the study of sinusitis have been the limited access to human sinuses and the lack of a satisfactory animal model that compares favorably with disease in man. Allergic rhinitis, a disease affecting 20 percent of Americans, is considered a major contributing factor to the development of sinusitis. We have developed a mouse model of acute sinusitis. We present data demonstrating the development of acute sinusitis in C57B1/6 and BALB/c mice after instillation ol Streptococcus pneumoniae (S. pneumoniae) (the most common pathogen responsible for acute sinusitis in man), the development of allergic rhinosinusitis in BALB/c mice, and augmentation of infection and of the inflammatory response to infection in BALB/c mice with simultaneous ongoing allergic reactions. With this model, we propose to investigate the interrelationship of allergic rhinitis and sinusitis. Our hypothesis is that the allergic response in the nose affects both the innate immune response and the host?s inflammatory response to clear the infection. Furthermore, we hypothesize that IL-4 released by Th2 cells recruited during the allergic reaction interferes with the recruitment, development, and activation of Th1 cells that contribute to the suppression of infection and inflammation caused by bacterial infection. To test these hypotheses, we propose the following specific aims. In Aim 1, we will investigate the relative importance of the innate immune system and the acquired immune system (i.e., Th1 cells) in reducing the infection arid sinus mucosal inflammation caused by intranasal inoculation of S. pneumoniae. In Aim 2, we will investigate whether Th2 cells are the component of the allergic response that leads to a more severe sinus infection after inoculation with S. pneumoniae. In Aim 3, we will investigate whether the exaggerated response to infection caused by the mucosal allergic response is due to a cytokine imbalance induced by Th2-type cytokines. By manipulating our animal model of sinusitis and exploiting the advantages of using knockout and transgenic mice, we will further increase our understanding of sinusitis and the host factors that contribute to this common disease. Our unique murine model provides the first opportunity to study this major health care problem at a level that was previously unavailable and that could lead to the identification of new treatments.

R21AI047916

2001-09-01

2003-08-31